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Three Part Question

In [patients undergoing coronary arterial bypass grafting] does [tranexamic acid] administration [compromise graft patency]?

Clinical Scenario

You have referred a patient with unstable angina who is on aspirin and a heparin infusion. You take him to theatre for CABG and the anaesthetist gives him tranexamic acid 2g on induction and 1g after completion of CPB. After straightforward quadruple bypass grafts he comes off bypass with ease and is transferred to the intensive care unit without any inotropic support. Two hours later the patient develops ST elevation in the inferior leads. Though the patients is haemodynamically stable, a balloon pump is inserted and as arrangements are being made to take him back for re-exploration, the ECG changes revert back to normal and remain so subsequently. Two months later you review this patient who is still getting some angina. An angiogram reveals that two of the vein grafts are now blocked. You wonder whether it was the tranexamic acid that might have caused this complication.

Search Strategy

Medline 1966-March 2004 using the Ovid interface.
[exp Cardiovascular surgical procedures/ OR cardiovascular surgical procedures.mp OR exp Thoracic surgery/ OR Thoracic surgery.mp OR exp Coronary Artery bypass/ OR coronary artery bypass surgery.mp OR CABG.mp OR coronary surgery.mp OR cardiac surgery.mp OR revascularization.mp ] AND [exp Tranexamic acid/ OR tranexamic.mp OR cyklokapron.mp]
Cochrane database of Systematic Reviews, ACP Journal Club and the Database of Abstracts of Reviews of Effects: search performed using keyword Tranexamic acid in the title

Search Outcome

127 papers were found in Medline and an additional 207 abstracts were found in the Cochrane database. 16 papers were selected for full review but 4 papers were rejected due to inadequate data on thrombotic complications [1-4]. The 12 remaining papers are presented in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Fremes et al, 1994, Canada	Medline search of English language PRCTs from Jan 1980 to June 1993 13 Desmopressin trials, 2 E-aminocaproic acid (EACA) trials , 2 tranexamic acid trials and 16 aprotinin trials	Meta-analysis level 1a	Mediastinal blood loss	EACA or TXA trials Mean 225mls less drainage than placebo (30% reduction) P<0.0001 Aprotinin 251ml less than placebo (36% reduction) p<0.0001	Only 2 tranexamic acid trials English only papers, no Embase search, expert consultation or grey literature review Prothrombotic events was not collected due to inconsistent reporting
			Perioperative mortality	EACA or TXA trials Odds of mortality versus placebo is 0.79 (0.18-3.57) P=NS
Ovrum et al, 1993, Norway	200 patients undergoing CABG by single surgeon. Initially all patients received TXA, then after a patient had an acute thrombosis of all grafts the following 100 patients had no TXA TXA group: 40mg/kg of TA after CPB Control group:(100 pts) no placebo	Retrospective cohort study (level 4 )	Bleeding	TXA group: 565±239mls Control group: 656±257mls p=0.002	Despite considerable overlap in the standard deviations of the two figures given for bleeding a significant p value was found, suggesting skewed data. Extreme bias introduced by having the control group after the TXA group, when it is likely that the surgeon will pay extra attention to graft patency.
			Thrombotic complications	TXA group: 5 MIs Control group: 1 MI p=0.1. 1 CVA in each group
Casati et al, 2001, Italy	40 patients undergoing off pump CABG. TXA group: 20 pts tranexamic acid (bolus of 1g before skin incision, followed by continuous infusion of 400 mg/hr during surgery) Control group: 20 patients received saline	Double blind PRCT (level 2b)	Total bleeding	TXA group: 400mls (338-485) Control group: 650mls (550-875) P<0.0001	Graft patency not studied, no thrombotic complications Study too small to evaluate difference in thrombotic complications
			Thrombotic complications	No thrombotic complications in either group
Jares et al, 2003, Czech Republic	49 patients CABG off pump TXA group: (23pts) (bolus of 1 g before surgical incision, followed by infusion 200mg/hour during surgery) Control group: 26 patients were enrolled into a control group	PRCT (level 2b)	Postoperative blood loss at 24 hours, transfusion requirements of packed red blood cells	TXA group: 420mls (330-530mls) Control group 550mls (500-650mls) P<0.01	Grafts not studied angiographically Study too small to exclude difference in thrombotic events
			Transfusion required	TXA group: 9% of pts Control group 28% of pts
			postoperative thrombotic events	Tranexamic acid was not associated with a higher incidence of myocardial ischemia or other thrombotic events
Pleym et al, 2003, Norway	80 1st time CABG patients taking aspirin until surgery TXA group: tranexamic acid 30mg/kg, bolus injection prior to CPB Control group: placebo (0.9% NaCl)	Double blind PRCT (Level 1b)	Blood loss at 16 hrs	TXA group 475mls (SD274mls) Control group 713mls (SD 243mls) P<0.001	Graft patency and thrombo embolic problems not studied
			Thrombotic events	One patient in the control group had a PE. No other mortality or complications
Casati et al, 2001, Italy	1040 consecutive patients undergoing elective cardiac operations at one centre. Aprotinin group: 518pts received 280mg pre-incision, 280mg in prime, and 70mg hr intraoperatively TXA group: 522pts received 1g pre-incision, 500mg in prime, and 400mg/hr intraoperatively	Unblinded PRCT (level 1b)	Post-opertative bleeding	Aprotinin group: 250ml (150-400ml) TXA group: 300ml (200-450ml) P=NS. Sample size calculation concluded that 500 pts were required in each group to exclude a difference of more than 50mls bleeding.	Well conducted study, however protocol for collection of thrombotic complication data not fully described in terms of definition and follow up time frames
			Re-exploration for surgical bleeding	TXA group: 7pts Aprotinin 5pts
			Thrombotic complications TXA vs Aprotinin groups	Perioperative MI 11 pts vs 9 pts. Early re-op for ischemia 3 pts vs 3 pts. PE 1pt vs 0pts Death 10pts vs 12 pts. Neurological dysfunction 4 pts vs 4 pts
Bernet et al, 1999, Switzerland	56 patients undergoing CABG who were still on Aspirin Aprotinin group full dose aprotinin TXA group: 10gm TXA over 20 min before sternotomy	Double blind PRCT (level 2b)	Postoperative blood loss	Aprotinin group: 840 ml in 24 hrs TXA group 880 ml/24 hours p = 0.481	Graft patency not studied No thrombotic complications
			Thrombotic complications	No perioperative myocardial infarction, pulmonary embolism, cerebrovascular event, or other thrombotic events
Karski et al, 1998, Canada	150 Patients received TXA 50 (n = 50),100 (n = 50), or 150 (n = 50) mg/kg intravenously before CPB with mild systemic hypothermia 32 c	Double blind PRCT (level 2b)	Blood loss	Blood loss at 6 hours and total hemoglobin loss was statistically greater in the 50-mg/kg group compared with the other two groups (p = 0.03; p = 0.02)	No thrombotic rates or graft patency rates studied
			Thrombotic complications	Not documented
Mongan 1998 USA	150 adult Patients undergoing primary CABG Either TXA (2 g) or large-dose aprotinin (7 million KIU). Plus 30 untreated patients for control.	Double Blind PRCT (level 2b).	Chest drain loss and allogenic transfusion was compared between 3 groups	No difference between groups in chest drain loss or transfusion requirements. No deaths , one patient in the aprotinin group had a stroke.	No thrombotic rates or graft patency rates studied.
			New myocardial infarctions	Aprotinin group 2 MIs. TXA group 3 MIs.
Lambert et al, 1995, Canada	220 patients undergoing CABG Low dose TXA: 20mg/kg over 30 mins on induction Medium Dose TXA: 50mg/kg High Dose TXA: 100mg/kg	Double blind PRCT (Level 2b)	Blood loss	Low dose TXA: 1032±358ml Medium dose TXA: 1067±502ml High dose TXA: 945±459mls. P=NS	No specific MI rates studied, no increase in complication rate
			Thrombotic complications	1 low dose and 2 high dose patients had a stroke, 2 medium dose patients died
Hardy et al 1998 Canada	134 patients undergoing elective CABG TXA group: high-dose tranexamic acid (10g bolus + placebo infusion) EACA group: Received epsilon-aminocaproic acid (15-g bolus + infusion of 1 g/h) Control group: Placebo infusions	Double blind PRCT (level 2b)	Blood loss	TXA group: 438ml(0-2675mls) EACA group: 538ml (0-3275mls) Control group: 700ml(75-3000ml) p<0.05 versus control	Thrombotic rates and graft patency not studied
			Thrombotic complications	2 deaths in EACA group, 1 CVA in TXA group. 2 MIs in EACA and control groups and 1 MI in TXA group
Brown et al, 1997, USA	91 patients undergoing elective CABG Pre-CPB TXA: 15mg/kg pre-CPB , 1mg/kg/hr during CPB and post CPB for 5 hrs Post CPB TXA: 15mg/kg post CPB then infusion of 1mg/kg/hr for 5 hrs Control group: Placebo infusions	Double blind PRCT (level 2b)	24hr mediastinal chest tube drainage	Pre-CPB TXA: 600ml (550-650ml) Post-CBA TXA: 1000ml (550-1500) Control: 1200ml (950-1700) p<0.005	No difference in thombotic complications, graft patency not studied
			Thrombotic complications	1 death in post-CPB group, no strokes, and no Q-wave MIs.

Comment(s)

One meta-analysis, one cohort study and 10 prospective randomized controlled trials were found that documented studies comparing tranexamic acid (TXA) to either aprotinin or placebo with documentation of thrombotic complications. The meta-analysis by Fremes et al was performed in 1994 and found only 2 papers on tranexamic acid. They found that either E-aminocaproic acid or tranexamic acid reduced bleeding by 30% and found no increase in perioperative myocardial infarction. The only study that highlighted anxiety over the safety of tranexamic acid was the cohort study by Ovrum et al published in 1993. Ovrum routinely used TXA until a patient had an acute thrombosis of all her grafts and adjacent native coronaries. He stopped using it and analysed the results of his next 100 patients compared to the previous 100. He had 5 MIs with TXA but only 1 MI without TXA, which was not statistically significant. This is a retrospective, single surgeon study, with extreme bias introduced by a surgeon who will almost certainly be taking far more care with his anastomoses after this change in practise. The largest PRCT was by Casati et al who compared aprotinin to tranexamic acid in 1040 primary elective CABG patients. They found no difference in bleeding, re-operation for bleeding, transfusion or outcome. In addition they documented no difference in perioperative MI, early reoperation for ischaemia, PE, neurological dysfunction or death, although the numbers of positive patients in each of these categories was small. They concluded that tranexamic acid was clinically as effective as aprotinin and was available at a fraction of the cost. 5 PRCTs compared tranexamic acid to placebo. 4 of the 5 clearly showed a reduction in bleeding rates. None of the studies investigated graft patency, but other outcome measures such as MI, PE , and neurological dysfunction were reported, and no concerns were raised as to the safety of tranexamic acid. It is important to note that the incidence of thrombotic complications is low and thus all of these studies are underpowered to exclude the possibility of increased thrombotic complications as the largest was in less than 150 patients. Thus it is clear that tranexamic acid reduces the incidence of post-operative bleeding, and only 1 cohort study has raised any concern over its safety in terms of thrombotic complications. No study has looked at vein graft patency after tranexamic acid directly.

Clinical Bottom Line

Tranexamic acid clearly reduces blood loss, requirement for blood transfusion, and the risk of reoperation for bleeding, and although no study has yet looked directly at vein graft patency with tranexamic acid, no randomized studies have raised concerns over its safety.

References

1. Pinosky ML, Kennedy DJ, Fishman RL et al. Tranexamic acid reduces bleeding after cardiopulmonary bypass when compared to epsilon aminocaproic acid and placebo. J Card Surg 1997;12(5):330-338.
2. Armellin G. Vinciguerra A. Bonato R. Pittarello D. Giron GP. Tranexamic acid in primary CABG surgery: high vs low dose. Minerva Anestesiologica 2004;70(3):97-107.
3. Barrons RW, Jahr JS. A Review of Post--Cardiopulmonary Bypass Bleeding, Aminocaproic Acid, Tranexamic Acid, and Aprotinin. American Journal of theraputics 1996;3:821-838.
4. Coffey A, Pittmam J, Halbrook H, Fehrenbacher J, Beckman D, Hormuth. The use of tranexamic acid to reduce postoperative bleeding following cardiac surgery: a double-blind randomized trial. Am. Surg 1995;61(7):566-568.
5. Fremes SE, Wong BI, Lee E, Mai R, Christakis GT, McLean RF, Goldman BS, Naylor CD. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994;58(6):1580-1588.
6. Ovrum E, Am HE, Abdelnoor M, Oystese R, Ringdal ML. Tranexamic acid (Cyklokapron) is not necessary to reduce blood loss after coronary artery bypass operations.[see comment]. J Thorac Cardiovasc Surg 1993;105(1):78-83.
7. Casati V, Gerli C, Franco A, Torri G, D'Angelo A, Benussi S, Alfieri O. O Tranexamic acid in off-pump coronary surgery: a preliminary, randomized, double-blind, placebo-controlled study. Ann Thorac Surg 2001;72(2):470-475.
8. Jares M, Vanek T, Straka Z, Brucek P. Tranexamic acid reduces bleeding after off-pump coronary artery bypass grafting. J Cardiovasc Surg 2003;44(2):205-208.
9. Pleym H, Stenseth R, Wahba A, Bjella L, Karevold A, Dale O. Single-dose tranexamic acid reduces postoperative bleeding after coronary surgery in patients treated with aspirin until surgery.[see comment]. Anesth Analg 2003;96(4):923-928.
10. Casati V, Bellotti F, Gerli C et al. Tranexamic acid administration after cardiac surgery: a prospective, randomized, double-blind, placebo-controlled study. Anesthesiology 2001;94(1):8-14.
11. Bernet F, Carrel T, Marbet G, Skarvan K, Stulz P. Reduction of blood loss and transfusion requirements after coronary artery bypass grafting: similar efficacy of tranexamic acid and aprotinin in aspirin-treated patients. J Card Surg 1999;14(2):92-97.
12. Karski JM, Dowd NP, Joiner R et al. The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic hypothermia (32 degrees C). J Cardiothorac Vasc Anesth 1998;12(6):642-646.
13. Mongan PD, Brown RS, Thwaites BK. Tranexamic acid and aprotinin reduce postoperative bleeding and transfusions during primary coronary revascularization. Anesth. Analg. 1998;87(2):258-265.
14. Lambert W, Brisebois FJ, Wharton TJ, Carrier RC, Boyle D, Rowe BH. The effectiveness of low dose tranexamic acid in primary cardiac surgery. Can J Anaesth 1998;45(6):571-574.
15. Hardy JF, Belisle S, Dupont C, Harel F, Robitaille D, Roy M, Gagnon L. Prophylactic tranexamic acid and epsilon-aminocaproic acid for primary myocardial revascularization. Ann Thorac Surg 1998;65(2):371-376.
16. Brown RS, Thwaites BK, Mongan PD. Tranexamic acid is effective in decreasing postoperative bleeding and transfusions in primary coronary artery bypass operations: a double-blind, randomized, placebo-controlled trial. Anesth Analg 1997;85(5):963-970.